Pramlintide
{{Short description|Diabetes medication}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 409738322
| IUPAC_name =
| image = Pramlintide sequence.svg
| width = 300
| caption = Golden line indicates disulfide bond
| tradename = Symlin
| Drugs.com = {{drugs.com|monograph|symlin}}
| MedlinePlus = a605031
| pregnancy_AU =
| pregnancy_US = C
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK =
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Subcutaneous
| bioavailability = 30 to 40%
| protein_bound = ~60%
| metabolism = Renal
| elimination_half-life = ~48 minutes
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 151126-32-8
| ATC_prefix = A10
| ATC_suffix = BX05
| PubChem = 16132446
| IUPHAR_ligand = 7482
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB01278
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = D3FM8FA78T
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D05595
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201669
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 44241191
| C=171 | H=267 | N=51 | O=53 | S=2
| smiles = CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N2CCC[C@H]2C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc3ccc(cc3)O)C(=O)N)NC(=O)[C@@H]4CCCN4C(=O)CNC(=O)[C@H](Cc5ccccc5)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](Cc6cnc[nH]6)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc7ccccc7)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)NC(=O)[C@@H]8CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N8)[C@@H](C)O)C)[C@@H](C)O)CC(=O)N)NC(=O)[C@H](CCCCN)N
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = TZIRZGBAFTZREM-MKAGXXMWSA-N
}}
Pramlintide (trade name Symlin) is an injectable amylin analogue drug for diabetes (both type 1 and 2), developed by Amylin Pharmaceuticals (now a wholly owned subsidiary of AstraZeneca).{{cite web | url=http://www.pmlive.com/pharma_news/astrazeneca_buys_bms_out_of_diabetes_alliance_528427 | title=AstraZeneca buys BMS out of diabetes alliance | date=19 December 2013 | access-date=16 June 2014 | vauthors = Taylor P }} Pramlintide is sold as an acetate salt.
Pharmacology
Pramlintide is an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β cells of the pancreas along with insulin after a meal.{{cite journal | vauthors = Jones MC | title = Therapies for diabetes: pramlintide and exenatide | journal = American Family Physician | volume = 75 | issue = 12 | pages = 1831–1835 | date = June 2007 | pmid = 17619527 | url = http://www.aafp.org/afp/2007/0615/p1831.pdf }} Like insulin, amylin is completely absent in individuals with Type I diabetes.{{cite journal | vauthors = Edelman S, Maier H, Wilhelm K | title = Pramlintide in the treatment of diabetes mellitus | journal = BioDrugs | volume = 22 | issue = 6 | pages = 375–386 | year = 2008 | pmid = 18998755 | doi = 10.2165/0063030-200822060-00004 | s2cid = 34608423 }}
In synergy with endogenous amylin, pramlintide aids in the regulation of blood glucose by slowing gastric emptying, promoting satiety via hypothalamic receptors (different receptors than for GLP-1), and inhibiting inappropriate secretion of glucagon, a catabolic hormone that opposes the effects of insulin and amylin. Pramlintide also has effects in raising the acute first-phase insulin response threshold following a meal.{{cn|date=November 2023}}
Both a reduction in glycated hemoglobin and weight loss have been shown in insulin-treated patients with type 2 diabetes taking pramlintide as an adjunctive therapy.{{cite journal | vauthors = Hollander P, Maggs DG, Ruggles JA, Fineman M, Shen L, Kolterman OG, Weyer C | title = Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients | journal = Obesity Research | volume = 12 | issue = 4 | pages = 661–668 | date = April 2004 | pmid = 15090634 | doi = 10.1038/oby.2004.76 | doi-access = free }}
Research Applications
In the research field, pramlintide has been experimented with and used as a potential treatment drug. Pramlintide has demonstrated its ability to decrease amyloid beta plaques in Alzheimer's disease mouse models.{{cite journal | vauthors = Tao Q, Zhu H, Chen X, Stern RA, Kowall N, Au R, Blusztajn JK, Qiu WQ | display-authors = 6 | title = Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease | journal = Journal of Alzheimer's Disease | volume = 62 | issue = 2 | pages = 597–609 | date = 2018 | pmid = 29480193 | pmc = 5956916 | doi = 10.3233/jad-170948 }}
Approval
Pramlintide has been approved on 3/16/2005 by the FDA, for use by type 1 and type 2 diabetic patients who use insulin.{{cite journal | vauthors = Ryan GJ, Jobe LJ, Martin R | title = Pramlintide in the treatment of type 1 and type 2 diabetes mellitus | journal = Clinical Therapeutics | volume = 27 | issue = 10 | pages = 1500–1512 | date = October 2005 | pmid = 16330288 | doi = 10.1016/j.clinthera.2005.10.009 }}{{subscription required}} Pramlintide allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating.
Apart from insulin analogs, pramlintide is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s.{{citation needed|date=March 2017}}{{Cite web|url=http://www.diabetes.org/newsroom/press-releases/2018/dual-hormone-artificial-pancreas-insulin-pramlintide-improves-glucose.html|title=Dual-Hormone, Artificial Pancreas with Insulin and Pramlintide Significantly Improves Glucose Levels, Compared to Insulin-Only Artificial Pancreas|website=American Diabetes Association|language=en|access-date=2018-08-28|archive-date=2018-08-29|archive-url=https://web.archive.org/web/20180829072111/http://www.diabetes.org/newsroom/press-releases/2018/dual-hormone-artificial-pancreas-insulin-pramlintide-improves-glucose.html|url-status=dead}}
Design and structure
{{more citations needed section|date=March 2017}}
Since native human amylin is highly amyloidogenic and potentially toxic, the strategy for designing pramlintide was to substitute residues from rat amylin, which is less amyloidogenic{{cite journal | vauthors = Palmieri LC, Melo-Ferreira B, Braga CA, Fontes GN, Mattos LJ, Lima LM | title = Stepwise oligomerization of murine amylin and assembly of amyloid fibrils | journal = Biophysical Chemistry | volume = 180-181 | pages = 135–144 | date = 2013 | pmid = 23974296 | doi = 10.1016/j.bpc.2013.07.013 }}{{cite journal | vauthors = Erthal LC, Marques AF, Almeida FC, Melo GL, Carvalho CM, Palmieri LC, Cabral KM, Fontes GN, Lima LM | display-authors = 6 | title = Regulation of the assembly and amyloid aggregation of murine amylin by zinc | journal = Biophysical Chemistry | volume = 218 | pages = 58–70 | date = November 2016 | pmid = 27693831 | doi = 10.1016/j.bpc.2016.09.008 }} but presumably retains clinical activity. Proline residues are known to be structure-breaking{{clarify|date=April 2023}} residues, so these were directly grafted into the human sequence. Despite its enhanced stability compared to human amylin, however, pramlintide is still able to organize into amyloid material.{{cite journal | vauthors = da Silva DC, Fontes GN, Erthal LC, Lima LM | title = Amyloidogenesis of the amylin analogue pramlintide | journal = Biophysical Chemistry | volume = 219 | pages = 1–8 | date = December 2016 | pmid = 27665170 | doi = 10.1016/j.bpc.2016.09.007 }}
Amino acid sequences:
| class="wikitable" | |
| Pramlintide | KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-(NH2) |
| Amylin | KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY-(NH2) |
| Rat amylin | KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-(NH2) |
Pramlintide is a positively charged protein.{{cn|date=April 2023}}
References
{{reflist}}
External links
- [http://www.symlin.com www.symlin.com] - product website
- [http://www.amylin.com/pipeline/symlin.cfm www.amylin.com] - Symlin page on the Amylin Pharmaceuticals website
{{Oral hypoglycemics and insulin analogs}}
Category:Amylin receptor agonists